hydrazines - cdc

A-1 HYDRAZINES

APPENDIX A

ATSDR MINIMAL RISK LEVEL

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C.

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L.

99-4991, requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop

jointly with the US. Environmental Protection Agency (EPA), in order of priority, a list of hazardous

substances most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare

toxicological profiles for each substance included on the priority list of hazardous substances; and

assure the initiation of a research program to fill identified data needs associated with the substances.

The toxicological profiles include an examination, summary, and interpretation of available

toxicological information and epidemiologic evaluations of a hazardous substance. During the

development of toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and

sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a

specific duration for a given route of exposure. An MRL is an estimate of the daily human exposure

to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health

effects over a specified duration of exposure. MRLs are based on noncancer health effects only and

are not based on a consideration of cancer effects. These substance-specific estimates, which are

intended to serve as screening levels, are used by ATSDR health assessors to identify contaminants

and potential health effects that may be of concern at hazardous waste sites. It is important to note

that MRLs are not intended to define clean-up or action levels.

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty

factor approach. They are below levels that might cause adverse health effects in the people most

sensitive to such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate

(15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of

exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not

yet identified a method suitable for this route of exposure. MRLs are generally based on the most

sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects

(such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for

establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will

occur.

A-2 HYDRAZINES APPENDIX A

MRLs are intended only to serve as a screening tool to help public health professionals decide where

to look more closely. They may also be viewed as a mechanism to identify those hazardous waste

sites that are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty

because of the lack of precise toxicological information on the people who might be most sensitive

(e.g., infants, elderly, nutritionally or immunologically compromised) to the effects of hazardous

substances. ATSDR uses a conservative (i.e., protective) approach to address this uncertainty

consistent with the public health principle of prevention. Although human data are preferred, MRLs

often must be based on animal studies because relevant human studies are lacking. In the absence of

evidence to the contrary, ATSDR assumes that humans are more sensitive to the effects of hazardous

substance than animals and that certain persons may be particularly sensitive. Thus, the resulting

MRL may be as much as a hundredfold below levels that have been shown to be nontoxic in

laboratory animals.

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within

the Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews,

with participation from other federal agencies and comments from the public. They are subject to

change as new information becomes available concomitant with updating the toxicological profiles.

Thus, MRLs in the most recent toxicological profiles supersede previously published levels. For

additional information regarding MRLs, please contact the Division of Toxicology, Agency for Toxic

Substances and Disease Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333.


MINIMAL RISK LEVEL WORKSHEETS Chemical Name: Hydrazine CAS Number: 302-01-2 Date: September 5, 1996 Profile Status: Draft 3 Route: [X] Inhalation [ ] Oral Duration: [ ] Acute [X] Intermediate [ ] Chronic Graph Key: 19 Species: mouse

Minimal Risk Level: 4 x10-3 ppm [ ] mg/kg/day [X] ppm

Reference: Haun and Kinkead 1973

Experimental design:(human study details or strain, number of animals per exposure/control groups, sex, dose administration details): 40 female ICR mice per group, exposed by inhalation to 0, 0.2, or 1.0 ppm continuously for 6 months.

Effects noted in study and corresponding doses: Moderate to severe fatty liver changes were seen at both exposure levels.

Calculations: LOAEL(HEC)= LOAEL x [(VA/BW)A÷ (VA/BW)H] LOAEL(HEC)= LOAEL x [(VA/BW)A÷ (VA/BW)H] LOAEL(HEC) = 0.2 ppm x [(0.043 m3/day ÷ 0.026 kg) ÷ (20 m3/day ÷ 70 kg)] LOAEL(HEC) = 1.154 ppm

MRL = LOAEL(HEC)÷Uncertainty Factor MRL = 1.154 ppm ÷300 MRL=4x 10-3ppm

Dose and endpoint used for MRL derivation:

[ ] NOAEL [X] LOAEL

Uncertainty Factors used in MRL derivation:

[X] 10 for use of a LOAEL [X] 3 for extrapolation from animals to humans following conversion to HEC [X] 10 for human variability

Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: No

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: VA mouse = 0.043 m3/day, BW = 0.026 kg


VA human = 20 m3/day, BW = 70 kg

Other additional studies or pertinent information which lend support to this MRL: The authors (Haun and Kinkead 1973) also investigated the effects of inhaled hydrazine in other species. Fatty liver changes were also observed in dogs exposed to 1 ppm hydrazine for 6 months and in monkeys exposed to 0.2 ppm for 6 months.

Agency Contact (Chemical Manager): Hugh Hansen

Agency Review Date: 1° review:___________ 2° review:_____________


Chemical Name: 1,1 -Dimethylhydrazine CAS Number: 57-14-7 Date: September 5, 1996 Profile Status: Draft 3 Route: [X] Inhalation [ ] Oral Duration: [ ] Acute [X] Intermediate [ ] Chronic Graph Key: 17 Species: mouse

Minimal Risk Level: 2 x 10-4 [ ] mg/kg/day [X] ppm

Reference: Haun et al. 1984

Experimental design:(human study details or strain, number of animals per exposure/control groups, sex, dose administration details): Groups of 400 female C57BL/6 mice per group, exposed by inhalation to 0, 0.05, 0.5, or 5 ppm for 6 months, 5 days per week, 6 hours per day.

Effects noted in study and corresponding doses: Hyaline degeneration in the gallbladder was significantly increased in the 0.05, 0.5, and 5 ppm groups compared to controls. Thus, the LOAEL is set at 0.05 ppm. Calculations:

LOAEL(HEC) = LOAEL(ADJ)x [ (VA/BW)A÷ (VA/B W)H] LOAEL(HEC) = (0.05 ppm x 6 hr/24 hr x 5 d/7 d) x [(VA/BW)A + (VA/BW)H] LOAEL(HEC) = 0.0089 ppm x [(0.043 m3/day ÷ 0.026 kg) ÷20 m3/day + 70 kg)] LOAEL(HEC)= 0.05 ppm

MRL = LOAEL(HEC)÷ Uncertainty Factor MRL = 0.05 ppm + 300 MRL = 2 x 10-4 ppm


[ ] NOAEL [X] LOAEL


[X] 10 for use of a LOAEL [X] 3 for extrapolation from animals to humans following conversion to HEC [X] 10 for human variability

Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: No

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: VA mouse = 0.043 m3/day, BW = 0.026 kg

VA human = 20 m3/day, BW = 70 kg


Other additional studies or pertinent information which lend support to this MRL: Studies of workers exposed to 1,1-dimethylhydrazine have reported changes indicative of a hepatic effect (elevated serum alanine aminotransferase activity, positive cephalin flocculation test) (Petersen et al. 1970; Shook and Cowart 1957). Angiectasis was observed in the livers of all exposed mice. Hepatic congestion was noted in mice exposed to 0.5 or 5 ppm 1,1-dimethylhydrazine (Haun et al. 1984). No NOAEL was identified.


Agency Review Date: 1° review:____________ 2°review:_____________


Chemical Name: 1,2-Dimethylhydrazine CAS Number: 540-73-8 Date: September 5, 1996 Profile Status: Draft 3 Route: [ ] Inhalation [X] Oral Duration: [ ] Acute [X] Intermediate [ ] Chronic Graph Key: 25 Species: mouse

Minimal Risk Level: 8 x 10-4 [X] mg/kg/day [ ] ppm

Reference: Visek et al. 199 1

Experimental design:(human study details or strain, number of animals per exposure/control groups, sex, dose administration details): 25 male mice per group, exposed to 0, 0.75, 1.6, or 2.7 mg/kg/day in the diet for 5 months. Although 2 diet preparations were administered (one containing 10% protein, the other containing 40% protein), the doses of 1,2-dimethylhydrazine were judged not to differ significantly between the two groups.

Effects noted in study and corresponding doses: Mild hepatitis and small decreases in body weight gain and relative organ weights were observed in mice exposed to the lowest dose (0.75 mg/kg/day). These effects were more severe in animals exposed to higher doses. For example, doses of 1.6 mg/kg/day produced frank toxic hepatitis, as characterized by lobular disorganization, hepatocellular hypertrophy, and centrilobular necrosis. Portal fibrosis and bile duct hyperplasia, two effects noted in only a few animals exposed to 1.6 mg/kg/day, were more frequently observed in animals receiving the highest dose (2.7 mg/kg/day). Calculations:

MRL = LOAEL ÷ Uncertainty Factor MRL = 0.75 mg/kg/day ÷1000 MRL = 8 x 10s4 mg/kg/day


[ ] NOAEL [X] LOAEL


[X] 10 for use of a LOAEL [X] 10 for extrapolation from animals to humans [X] 10 for human variability

Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: 0.058 mg/day (daily food intake provided by authors) ÷ 0.035 kg (body weight provided by authors) x 0.45 (molecular weight adjustment for use of dihydrochloride salt) = 0.75 mg/kg/day.


If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: N/A

Other additional studies or pertinent information which lend support to this MRL: Hepatic effects (hepatotoxicity, necrosis, fibrosis, hemosiderosis, ascites, cirrhosis, degeneration) have been observed in rats (Bedell et al. 1982), guinea pigs (Wilson 1976), dogs (Wilson 1976), and pigs (Wilson 1976) subchronically exposed to 4.2-30 mg/kg/day 1,2-dimethylhydrazine by the oral route.


Agency Review Date: 1° review:___________ 2°review:____________

B-1 HYDRAZINES APPENDIX B

USER’S GUIDE

Chapter 1

Public Health Statement

This chapter of the profile is a health effects summary written in non-technical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or chemical release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the chemical.

The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic.

Chapter 2

Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1, 2-2, and 2-3) and figures (2-l and 2-2) are used to summarize health effects and illustrate graphically levels of exposure associated with those effects. These levels cover health effects observed at increasing dose concentrations and durations, differences in response by species, minimal risk levels (MRLs) to humans for noncancer end points, and EPA’s estimated range associated with an upperbound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs).

The legends presented below demonstrate the application of these tables and figures. Representative examples of LSE Table 2-l and Figure 2-l are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure.

LEGEND

See LSE Table 2-l

(1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exists, three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-l) and oral (LSE Figure 2-2) routes. Not all substances will have data on each route of exposure and will not therefore have all five of the tables and figures.


(2) Exposure Period Three exposure periods - acute (less than 15 days), intermediate (15-364 days), and chronic (365 days or more) are presented within each relevant route of exposure. In this example, an inhalation study of intermediate exposure duration is reported. For quick reference to health effects occurring from a known length of exposure, locate the applicable exposure period within the LSE table and figure.

(3) Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the “System” column of the LSE table (see key number 18).

(4) Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the 2 “18r” data points in Figure 2-l).

(5) Species The test species, whether animal or human, are identified in this column. Section 2.5, “Relevance to Public Health,” covers the relevance of animal data to human toxicity and Section 2.3, “Toxicokinetics,” contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses to derive an MRL.

(6) Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 1 S), rats were exposed to 1 ,1,2,2-tetrachloroethane via inhalation for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review of the dosing regimen refer to the appropriate sections of the text or the original reference paper, i.e., Nitschke et al. 1981.

(7) System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. “Other” refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, 1 systemic effect (respiratory) was investigated.

(8) NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote “b”).

(9) LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study that caused a harmful health effect. LOAELs have been classified into “Less Serious” and “Serious” effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not derived from Serious LOAELs.

(10) Reference The complete reference citation is given in chapter 8 of the profile.


(11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses not causing measurable cancer increases.

(12) Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote “b” indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm.

LEGEND

See Figure 2-l

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure concentrations for particular exposure neriods.

(13) Exposure Period The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated.

(14) Health Effect These are the categories of health effects for which reliable quantitative data exists. The same health effects appear in the LSE table.

(15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log scale “y” axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in mg/kg/day.

(16) NOAEL In this example, 1% NOAEL is the critical endpoint for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote “b” in the LSE table).

(17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to the entry in the LSE table.

(18) Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from the EPA’s Human Health Assessment Group’s upper-bound estimates of the slope of the cancer dose response curve at low dose levels (ql*).

(19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure.


Chapter 2 (Section 2.5)

Relevance to Public Health

The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions.

1. What effects are known to occur in humans?

2 . What effects observed in animals are likely to be of concern to humans?

3 . What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites?

The section covers end points in the same order they appear within the Discussion of Health Effects by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included.

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed.

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Data Needs section.

Interpretation of Minimal Risk Levels

Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure.

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2.5, “Relevance to Public Health,” contains basic information known about the substance. Other sections such as 2.7, “Interactions with Other Substances,” and 2.8, “Populations that are Unusually Susceptible” provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology the Environmental Protection Agency (EPA) provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs).


To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential systemic, neurological, and developmental effects. If this information and reliable quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. When a NOAEL is not available, a lowest-observedadverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables.

hydrazines - cdc

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